What is the role of blood-brain-barrier regional specificity in the nucleus accumbens?

项目总结/摘要 血脑屏障（BBB）是描述中枢神经系统（CNS）独特性质的术语 这些血管允许它们严格地调节周围神经细胞的细胞外环境， 组织.虽然已知不同的大脑区域由不同的细胞类型组成，并执行不同的功能， 功能，目前尚不清楚BBB是否在功能不同的区域表现出不同的功能，以调节特定的功能。 神经回路由于对血脑屏障的异质性知之甚少，本项目将解决这一差距， 知识和追求的问题，是否区域专门化的血脑屏障可以调节 本地电路功能和行为。这将确定是否可以靶向BBB以调节特定行为， 包括奖励和上瘾 单细胞RNA测序显示，BBB存在显著的区域间异质性， 内皮细胞（EC）中的差异基因表达。虽然典型的BBB基因，有助于 限制性屏障特性在所有脑区的EC中表达，许多基因参与转运， 信号传导和代谢被发现在特定脑区域的EC中富集。例如，Stra 6， 视黄酸的转运调节剂，显着丰富的核壳（sNAc）和腹侧 耳蜗核（VCN）与大脑的其他区域相比。sNAc特别令人感兴趣，因为它 奖励和强化学习的功能暗示该区域与药物成瘾有关。由于流行和 由于成瘾的严重性，迫切需要找到治疗这一重大公共卫生问题的新目标， 询问BBB是否通过Stra 6在调节成瘾中发挥作用。 拟议的研究将通过确定（1）Stra 6在 血脑屏障对sNAc的发育或成人功能是必需的，（2）Stra 6通过什么样的分子机制 调节sNAc功能，以及（3）Stra 6是否是学习成瘾行为所必需的。这项提案将考验 Stra 6在sNAc内浓缩类维生素A，从而动态调节多巴胺受体的假设 水平，因此sNAc在空间学习和成瘾中的成人功能。Stra 6的重要性 将使用条件性EC特异性Stra 6敲除小鼠在发育期间切除Stra 6来测试BBB 或者成年后。这些目标还将测试增加膳食维生素A（类维生素A的来源）是否能 在缺乏Stra 6的情况下增加类维生素A水平并拯救sNAc功能。该提案的核心目标是 更深入地了解BBB对大脑功能的贡献，详细说明成瘾的机制， 评估哪些因素可能增加个体对药物成瘾的易感性。

PROJECT SUMMARY/ABSTRACT The blood-brain barrier (BBB) is a term that describes the unique properties of central nervous system (CNS) blood vessels which allow them to stringently regulate the extracellular environment of the surrounding neural tissue. While it is known that different brain regions are made up of diverse cell types and execute distinct functions, it is unknown if the BBB exhibits varied features in functionally distinct regions to regulate specific neural circuits. Since little is known about heterogeneity of the BBB, this project will address this gap in knowledge and pursue the question of whether regional specializations of the blood-brain barrier may regulate local circuit function and behavior. This will identify if the BBB could be targeted to modulate specific behaviors, including reward and addiction. Single cell RNA sequencing revealed that there is significant inter-regional heterogeneity of the BBB via differential gene expression in endothelial cells (ECs). While the canonical BBB genes that contribute to restrictive barrier properties were expressed in ECs across all brain regions, many genes involved in transport, signaling, and metabolism were found to be enriched in ECs of specific brain regions. For instance, Stra6, a transport regulator of retinoids, is remarkably enriched in the nucleus accumbens shell (sNAc) and the ventral cochlear nucleus (VCN) compared to other areas of the brain. The sNAc is particularly of interest because its function in reward and reinforcement learning implicates the region in drug addiction. Due to the prevalence and severity of addiction, it is urgently important to find new targets for treating this major public health issue by asking if the BBB, via Stra6, plays a role in regulating addiction. The proposed study will address this critical need by determining (1) if the regional specificity of Stra6 at the BBB is necessary for the development or adult function of the sNAc, (2) by what molecular mechanisms Stra6 regulates sNAc function, and (3) if Stra6 is required for learning addiction behavior. This proposal will test the hypothesis that Stra6 concentrates retinoids within the sNAc, thereby dynamically regulating dopamine receptor levels and thus the adult function of the sNAc in both spatial learning and addiction. The importance of Stra6 at the BBB will be tested using conditional, EC-specific Stra6 knockout mice to excise Stra6 during development or in adulthood. These aims will also test whether elevating dietary Vitamin A, the source of retinoids, can increase retinoid levels in the absence of Stra6 and rescue sNAc function. The central goals of this proposal are to gain deeper understanding of the BBB’s contribution to brain function, specify mechanisms of addiction, and assess what factors might increase individual susceptibility to drug addiction.